TOPICALLY ACTIVE OCULAR CARBONIC-ANHYDRASE INHIBITORS - NOVEL BISCARBONYLAMIDOTHIADIAZOLE SULFONAMIDES AS OCULAR HYPOTENSIVE AGENTS

A novel homologous series of bis(carbonyl)amidothiadiazole sulfonamide s has been synthesized for structure-activity relationship studies, an d initial characterization has been performed. The goal was synthesis of thiadiazole derivatives with appropriate lipid and water solubiliti es for utility as topically (corneal application) active carbonic anhy drase (CA) inhibitors. This series has solubility properties and pK(a) which bracket those of acetazolamide-the prototypical CA inhibitor. A ll of these compounds are active as in vitro CA inhibitors, and are 10 -25% as potent as acetazolamide as in vitro enzyme inhibitors. Two of these compounds act as ocular hypotensive agents after topical applica tion of a single dose to the corneas of normotensive New Zealand albin o rabbits. The efficacy of the lead compound of this series (in this o ne model) is approximately equivalent to that of topical CA inhibitors that are presently in clinical trial. None of these novel compounds r eacts to an appreciable extent with free sulfhydryl groups (a predicto r of toxicity). This family of compounds will be useful for future stu dies of ocular pharmacokinetics, as well as ocular and systemic effect s of topical administration of CA inhibitors. These and future studies may lead to development of thiadiazole sulfonamides useful in the man agement of glaucoma.